CN113368254A - PH response type size self-regulation nano-drug delivery system and preparation method thereof - Google Patents
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Abstract
The invention belongs to the technical field of tumor targeted therapeutic drugs, and particularly discloses a pH response type size self-regulating nano-drug delivery system and a preparation method thereof. The nano drug delivery system comprises Glucose Oxidase (GOD) and glucose oxidase IIIIron (Fe) ions3+) And MnO with positive charge2The formed nano particles have the particle size of 81.4 +/-4.2 nm, can complete long-acting in-vivo circulation to ensure effective penetration of tumor blood vessels, then disintegrate after reaching the weak acid environment of tumor tissues, and decompose from the original size of 81.4 +/-4.2 nm into ultra-small nano particles of 20-30nm, thereby obtaining deeper tumor tissue penetration capacity, solving the size contradiction between long-acting in-vivo circulation and deep penetration of tumor tissues, and realizing size self-regulation and high-efficiency delivery. The nano particles formed by the drug delivery system after drug loading have uniform particle size, small diameter, good dispersion and no agglomeration, and are beneficial to improving the treatment effect; and the preparation method is simple and convenient for industrial production.
Description
Technical Field
The invention relates to the technical field of tumor targeted therapy drugs, in particular to a pH response type size self-regulation nano-drug delivery system and a preparation method thereof.
Background
In recent years, with the development of nano biotechnology, the development and clinical transformation of nano drug delivery systems have made great progress. At present, the nano-drug delivery systems such as paclitaxel-liposome (lipitor), paclitaxel-albumin nano-particle (Abraxane), adriamycin-liposome (Kailai and Ribaoduo), G-CSF-polyethylene glycol nano-particle (Lonqux) and fluorouracil-polylactic acid nano-particle (Zhongren Fluan) applied to clinical application can improve the drug curative effect to a certain extent and reduce the toxic and side effects. However, when the nano drug delivery system treatment is performed, the primary tumor focus is temporarily inhibited and is easy to metastasize or recur again.
An important reason for this phenomenon is that the existing nano-drug delivery systems have difficulty deeply penetrating into tumor tissues after entering the body. Nanoparticles with the size of about 100nm generally have longer in vivo circulation half-life and higher tumor vessel penetration rate, however, due to the dense extracellular matrix of tumor tissues and the overhigh hydraulic pressure of interstitial space, the nanoparticles can only penetrate through several cell layers near the tumor vessels and cannot deeply penetrate into the central area of the tumor tissues; nanoparticles between 20-30nm in size have a greater ability to penetrate deep into tumor tissue, however their application is limited by a shorter in vivo circulating half-life and a lower tumor vascular penetration rate. The size mismatch required for the nanomedicine delivery system to achieve long-lasting in vivo circulation and deep penetration into tumor tissue is therefore an urgent problem to be solved.
Around the problem of the nano-size mismatch that is required for the nano-drug delivery system to complete long-acting in vivo circulation and deeply penetrate tumor tissues, researchers have actively conducted related studies. Hu designs a dendritic poly L-lysine micro-nanoparticle loaded with adriamycin and indocyanine green, the outer layer of the dendritic poly L-lysine micro-nanoparticle is covered with hyaluronic acid to form a nano system (see Biomaterials, volume 168, pages 64-75, (2018)), and the micro-nanoparticle is released under the enzymolysis action of hyaluronidase overexpressed in a tumor microenvironment and deeply permeates into tumor interstitium. Sun forms a grid to entrap taxol by crosslinking polyethylene glycol-metalloenzyme-2 lytic peptide and dextran to form a small copolymer micelle, an enzyme response type nanocluster is prepared (see ACS applied materials & interfaces, 11, 11865-11875 page, (2019)), and the nanocluster is dissociated under the action of extracellular matrix metalloproteinase-2 to release a small micelle with good tumor permeability, so that the drug is delivered to the deep part of a solid tumor. However, these studies mainly rely on complex and exquisite carrier designs to provide the nano delivery system with special functions, and have the problems of complex process, high cost, low drug killing power, and the like, which severely restricts the large-scale production and clinical application of the nano delivery system.
Disclosure of Invention
In view of the above drawbacks of the prior art, the present invention aims to provide a pH-responsive size self-regulating nano-drug delivery system and a preparation method thereof, wherein the nano-drug delivery system is a carrier-free drug delivery system, the preparation method is simple and easy to implement, the cost is low, the size can be self-regulated, the size contradiction problem between long-acting in vivo circulation and deep penetration into tumor tissue can be solved, and efficient delivery can be achieved.
To achieve the above and other related objects, a first aspect of the present invention provides a nano-drug delivery system comprising Glucose oxidase (Glucose Oxi)dase, GOD), ferric ion (Fe)3+) And MnO with positive charge2The nanoparticles formed.
Further, the nano-drug delivery system comprises Glucose Oxidase (GOD), ferric ion (Fe)3+) And MnO with positive charge2The three are formed into spherical nano particles through electrostatic attraction.
Further, the positively charged MnO2MnO for introducing amino group to surface2Nanoparticles, preferably, said MnO2The amino groups on the surface of the nanoparticles are formed by modification of polyallylamine hydrochloride.
Further, the particle size of the nano particles is 81.4 +/-4.2 nm.
Further, the nano-drug delivery system can be disintegrated and decomposed into ultra-small nano-particles of 20-30nm in a weak acid environment of tumor tissues.
In a second aspect, the present invention provides a method for preparing the nano-drug delivery system according to the first aspect, comprising the steps of:
(1) MnO of2Mixing the nanoparticle solution and a Glucose Oxidase (GOD) solution, reacting under the action of ultrasound, centrifuging after the reaction is finished, removing a supernatant, and re-suspending a precipitate with water to obtain a mixture 1;
(2) FeCl is added3·6H2Adding the O solution into the mixture 1, uniformly mixing under the action of ultrasound, and then stirring and reacting under the condition of keeping out of the sun to obtain a reaction solution 2;
(3) standing the reaction solution 2, taking out the precipitate after the reaction solution is completely precipitated, and dialyzing with water to obtain GOD-MnO2-Fe3+(GMF for short) nanoparticles, i.e. the said nano drug delivery system.
Further, in the step (1), the MnO2The concentration of the nano particle solution is 10 mg/ml; the concentration of the Glucose Oxidase (GOD) solution is 2 mg/ml.
Further, in the step (1), the reaction time is 15-30 min.
Further, in the step (2), the FeCl3·6H2The concentration of the O solution is 25-30 mg/ml.
Further, in the step (2), FeCl is added3·6H2And adding the O solution into the mixture 1, and shaking for 15-30min under ultrasonic wave to uniformly mix.
Further, in the step (2), the reaction time is 40-60min, preferably 45min, by stirring in the dark.
Further, in the steps (1) and (2), ultrasound is performed at normal temperature.
Further, in the step (3), the reaction solution 2 is allowed to stand for not less than 8 hours.
Further, in the step (3), the dialysis time is not less than 30 min.
As described above, the pH-responsive size self-regulating nano-drug delivery system and the preparation method thereof of the present invention have the following beneficial effects:
1. the pH response type dimension self-regulation nano-drug delivery system comprises Glucose Oxidase (GOD) and ferric ion (Fe)3+) And MnO modified to have a positive charge2The three are electrostatic attracted to form dense spherical nanoparticles with the particle size of 81.4 +/-4.2 nm, which can firstly support the nanoparticles to complete long-acting in vivo circulation so as to ensure effective penetration of tumor blood vessels, and then Fe reaches the weak acid environment of tumor tissues3+Dissociating, disintegrating the nano drug delivery system, and decomposing from the original 81.4 + -4.2 nm size to ultra-small nano particles MnO of 20-30nm2Thereby obtaining deeper tumor tissue penetration capacity, further solving the size contradiction between long-acting in vivo circulation and deep penetration of tumor tissue, and realizing the self-regulating and high-efficiency delivery of the size.
2. The pH response type size self-regulating nano-drug delivery system prepared by the method has the advantages of uniform particle size of nano-particles formed after drug loading, small diameter, good dispersion and no agglomeration, and is beneficial to improving the treatment effect.
3. The preparation method of the nano-drug delivery system has the advantages of easily obtained raw materials, simple operation, and convenient large-scale industrial production because the used equipment is conventional equipment.
Drawings
Fig. 1 is a schematic view showing an assembly process and a structure of a pH-responsive self-regulating nano-drug delivery system according to the present invention.
FIG. 2 is a graph showing the distribution of the particle size of the pH responsive self-regulating nanomedicine delivery system of the present invention, wherein the left graph shows the particle size of GMF nanoparticles and the right graph shows MnO2The particle size of the nanoparticles.
Fig. 3 shows the distribution of the pH-responsive dimensionally self-regulated nano-drug delivery system in example 1 in tumor tissue.
Detailed Description
The present invention is further described with reference to the following embodiments and drawings, and it is to be understood that other advantages and effects of the present invention can be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
The invention provides a pH response type dimension self-regulation nano-drug delivery system, as shown in figure 1, the nano-drug delivery system comprises Glucose Oxidase (GOD) and ferric ion (Fe)3+) And MnO modified to have a positive charge2(Poly(allylamine hydrochloride)-MnO2，PAH-MnO2) The three are formed into dense spherical nanoparticles (GMF for short) by electrostatic attraction, and the particle diameter of the nanoparticles is 81.4 +/-4.2 nm. Wherein, MnO2H capable of being generated in situ under weak acidic condition of tumor2O2Reaction to produce O2GOD can consume glucose at the tumor site while producing H2O2Further promote O2The two form a chain reaction. GOD and MnO2The reaction forms unstable flocs with Fe3+A stable grid-like composite is formed. Therefore, the nano-drug delivery system of the present invention can complete long-acting in vivo circulation to ensure effective penetration of tumor blood vessels, and then after reaching the weak acid environment of tumor tissues, Fe3+Dissociating, and disintegrating the nano-drug delivery system, from the most advancedThe initial size of 81.4 +/-4.2 nm is decomposed into ultra-small nano particles MnO of 20-30nm2Thereby obtaining deeper tumor tissue penetration capacity, further solving the size contradiction between long-acting in vivo circulation and deep penetration of tumor tissue, and realizing the self-regulating and high-efficiency delivery of the size.
The preparation method of the nano-drug delivery system provided by the invention comprises the following steps:
(1) MnO of2Mixing the nanoparticle solution and Glucose Oxidase (GOD) solution, reacting for 15-30min under the action of ultrasound, centrifuging after the reaction is finished, removing supernatant, and re-suspending the precipitate with water to obtain a mixture 1;
(2) FeCl is added3·6H2Adding the O solution into the mixture 1, vibrating for 15-30min under ultrasound to uniformly mix the O solution and the mixture, and then stirring and reacting for 40-60min under the condition of keeping out of the sun to obtain a reaction solution 2;
(3) standing the reaction solution 2, taking out the precipitate after the reaction solution is completely precipitated, and dialyzing with water to obtain GOD-MnO2-Fe3+(GMF for short) nanoparticles, i.e. the said nano drug delivery system.
Further, in the step (1), the MnO2The concentration of the nano particle solution is 10 mg/ml; the concentration of the Glucose Oxidase (GOD) solution is 2 mg/ml.
Further, in the step (2), the FeCl3·6H2The concentration of the O solution is 25-30 mg/ml.
Further, in the step (3), the reaction solution 2 is allowed to stand for not less than 8 hours.
Further, in the step (3), the dialysis time is not less than 30 min.
In the preparation method of the invention, the water used is selected from deionized water and ultrapure water; the ultrasonic treatment is carried out at normal temperature, and through the ultrasonic action, firstly, reactants can be uniformly mixed, and secondly, the generation of nanoparticles and the uniform particle size distribution of the nanoparticles can be promoted.
In the steps (1) and (2) of the production method of the present invention, the MnO may be2The nanoparticle solution is composed of MnO2The nano particles are uniformly dispersed in water to prepareThe Glucose Oxidase (GOD) solution is prepared by dissolving Glucose Oxidase (GOD) in water, and the FeCl is prepared3·6H2The O solution is made of FeCl3·6H2Dissolving O in water, and adding ultrasonic to assist dissolving. The nature of the three reagents and the methods of their solution formulation are known to those skilled in the art.
The present invention will be described in detail by way of examples. It is also to be understood that the following examples are illustrative of the present invention and are not to be construed as limiting the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art may be made in light of the above teachings. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.
Example 1
The preparation method of the pH-responsive self-regulating nano-drug delivery system (GMF) in this example is as follows:
1. modified positively charged MnO2Preparing nano particles: modification of MnO with polyallylamine hydrochloride (PAH)2The nano particles introduce amino groups on the surfaces thereof, and the specific method comprises the following steps:
74.8mg of PAH was weighed out and dissolved in 2mL of ultrapure water, 63.0mg of KMnO was weighed out4Dissolving in 18mL of ultrapure water; mixing PAH aqueous solution with KMnO4The aqueous solutions were mixed, magnetically stirred at room temperature for 15 minutes, ultra-high speed centrifuged (41kr/min, 4 ℃, 1 hour) with deionized water, and washed 3 times.
2. Dissolving 2mg GOD in 1ml deionized water, and mixing with 1ml 10mg/ml modified MnO with positive electricity2The nanoparticle solution was mixed in a 15ml centrifuge tube, reacted for 15min with ultrasonic vibration, centrifuged for 5min (10000rpm), the supernatant was removed, and the precipitate was resuspended in 1ml water to obtain mixture 1.
3. Taking 28.96mg FeCl3·6H2Dissolving O in 1ml water, adding into mixture 1 after ultrasonic assisted dissolution, shaking with ultrasonic cleaning instrument for 15min, and transferring into small containerStirring the mixture in a brown bottle in the dark for 45min to obtain a reaction solution 2.
4. Standing the reaction solution 2 overnight, taking out a reaction product, and dialyzing with deionized water for 30min to obtain GOD-MnO2-Fe3+(GMF) nanoparticles.
1mL of the product obtained in step 1 (MnO)2Nanoparticles), dialyzing the product obtained in the step 4 (GMF nanoparticles), and measuring MnO obtained by dialysis by using a Marven laser particle size analyzer2The average particle size and distribution of the nanoparticles and GMF nanoparticles are shown in fig. 2.
As can be seen from the particle size distribution diagram of FIG. 2, MnO2The particle size of the nano particles is 20-30nm, and the particle size of the GMF nano particles is 81.4 +/-4.2 nm. Example 2
The preparation method of the pH-responsive self-regulating nano-drug delivery system (GMF) in this example is as follows:
1. modified positively charged MnO2Preparing nano particles: same as in example 1.
2. 4mg GOD was dissolved in 1ml deionized water and mixed with 2ml 10mg/ml MnO2The nanoparticle solution was mixed in a 10ml centrifuge tube, reacted for 30min with ultrasonic vibration, centrifuged for 5min (10000rpm), the supernatant was removed, and the precipitate was resuspended in 2ml water to obtain mixture 1.
2. 57.92mg of FeCl are taken3·6H2Dissolving O in 1ml of water, adding the mixture 1 after ultrasonic assisted dissolution, shaking for 15min by an ultrasonic cleaner, and then transferring the mixture into a small brown bottle to stir and react for 60min in a dark place to obtain a reaction solution 2.
3. Standing the reaction solution 2 overnight, taking out a reaction product, and dialyzing with deionized water for 30min to obtain GOD-MnO2-Fe3+(GMF) nanoparticles.
Example 3
The preparation method of the pH-responsive self-regulating nano-drug delivery system (GMF) in this example is as follows:
1. modified positively charged MnO2Preparing nano particles: same as in example 1.
2. 4mg GOD was dissolved in 2ml deionized water and mixed with 2ml 10mg/ml MnO2Nano meterThe particle solution was mixed in a 10ml centrifuge tube, reacted for 30min with ultrasonic vibration, centrifuged for 5min (10000rpm), the supernatant was removed, and the precipitate was resuspended in 2ml water to obtain mixture 1.
2. 57.92mg of FeCl are taken3·6H2Dissolving O in 2ml of water, adding the mixture into the mixture 1 after ultrasonic assisted dissolution, vibrating for 15min by using an ultrasonic cleaner, and then transferring the mixture into a small brown bottle to stir and react for 60min in the dark to obtain a reaction solution 2.
3. Standing the reaction solution 2 overnight, taking out a reaction product, and dialyzing with deionized water for 30min to obtain GOD-MnO2-Fe3+(GMF) nanoparticles.
Application example
In vivo retention and tissue fluorescence studies were performed using MDA-MB-231 tumor-bearing nude mice (from the animal center of David university of Chongqing medicine). 200 μ L of GMF from example 1 (labeled with FITC for GOD, 2mg/kg relative to the injected amount) was injected into the tail vein when the tumor diameter was 6-8 mm. Tumor-bearing nude mice were anesthetized 4h and 12h after injection, and imaged using a small animal in vivo imager (excitation wavelength of 495nm and emission signal wavelength of 525nm), with the results shown in fig. 3. Fig. 3 shows the distribution of the pH-responsive dimensionally self-regulated nano-drug delivery system (GMF) in tumor tissue in example 1. As can be seen from fig. 3, GMF showed strong fluorescence (Low → High, indicating fluorescence intensity) in the tumor region 12h after the nano-drug delivery system entered the mouse, while the fluorescence of the main organ region was weak, indicating that GMF accumulated in the tumor region and released GOD.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. A nano-drug delivery system, comprising glucose oxidase GOD, ferric ion and a positive chargeMnO of load2The nanoparticles formed.
2. The nano-drug delivery system of claim 1, characterized in that: the nano drug delivery system comprises glucose oxidase GOD, ferric iron ions and MnO with positive charges2The three are formed into spherical nano particles through electrostatic attraction.
3. The nano-drug delivery system according to claim 1 or 2, characterized in that: the MnO having positive charge2MnO for introducing amino group to surface2Nanoparticles.
4. The nano-drug delivery system of claim 3, characterized in that: the MnO2The amino groups on the surface of the nanoparticles are formed by modification of polyallylamine hydrochloride.
5. The nano-drug delivery system of claim 1, characterized in that: the particle size of the nano particles is 81.4 +/-4.2 nm.
6. The nano-drug delivery system of claim 5, characterized in that: the nano-drug delivery system can be disintegrated and decomposed into ultra-small nano-particles of 20-30nm in a weak acid environment of tumor tissues.
7. The method for preparing a nano-drug delivery system according to any one of claims 1 to 6, comprising the steps of:
(1) MnO of2Mixing the nanoparticle solution and the glucose oxidase GOD solution, reacting under the action of ultrasound, centrifuging after the reaction is finished, removing supernatant, and re-suspending the precipitate with water to obtain a mixture 1;
(2) FeCl is added3·6H2Adding the O solution into the mixture 1, uniformly mixing under the action of ultrasound, and then stirring and reacting under the condition of keeping out of the sun to obtain a reaction solution 2;
(3) standing the reaction solution 2 until it isAfter complete precipitation, taking out the precipitate, dialyzing with water to obtain GOD-MnO2-Fe3+Nanoparticles, i.e. the nano drug delivery system.
8. The method of claim 7, wherein: in the step (1), the MnO2The concentration of the nano particle solution is 10mg/ml, and the concentration of the glucose oxidase GOD solution is 2 mg/ml;
and/or, in the step (2), the FeCl3·6H2The concentration of the O solution is 25-30 mg/ml.
9. The method of claim 7, wherein: in the step (1), the reaction time is 15-30 min.
10. The method of claim 7, wherein: in the step (2), FeCl is added3.6H2Adding the O solution into the mixture 1, and vibrating for 15-30min under ultrasonic to uniformly mix;
and/or in the step (2), stirring in the dark for 40-60 min;
and/or in the step (3), the standing time of the reaction solution 2 is not less than 8 hours;
and/or in the step (3), the dialysis time is not less than 30 min.
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